Samenvatting
Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI).
Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES.
Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease.
Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease.
| Originele taal-2 | English |
|---|---|
| Artikelnummer | e78469 |
| Aantal pagina's | 24 |
| Tijdschrift | eLife |
| Volume | 11 |
| DOI's | |
| Status | Published - 17-okt.-2022 |
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- 10.7554/eLife.78469Licentie: CC BY
- Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunityFinal publisher's version, 781 KBLicentie: CC BY
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Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity : A retrospective cohort study. / Hebert, Anne; Simons, Annet; Schuurs-Hoeijmakers, Janneke H.M. et al.
In: eLife, Vol. 11, e78469, 17.10.2022.Onderzoeksoutput › Academic › peer review
TY - JOUR
T1 - Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity
T2 - A retrospective cohort study
AU - Hebert, Anne
AU - Simons, Annet
AU - Schuurs-Hoeijmakers, Janneke H.M.
AU - Koenen, Hans J.P.M.
AU - Zonneveld-Huijssoon, Evelien
AU - Henriet, Stefanie S.V.
AU - Schatorjé, Ellen J.H.
AU - Hoppenreijs, Esther P.A.H.
AU - Leenders, Erika K.S.M.
AU - Janssen, Etienne J.M.
AU - Santen, Gijs W.E.
AU - de Munnik, Sonja A.
AU - van Reijmersdal, Simon V.
AU - van Rijssen, Esther
AU - Kersten, Simone
AU - Netea, Mihai G.
AU - Smeets, Ruben L.
AU - van de Veerdonk, Frank L.
AU - Hoischen, Alexander
AU - van der Made, Caspar I.
N1 - Funding Information: This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences. European Research Council No. 833247 Mihai G Netea ZonMw Spinoza Grant Mihai G Netea Radboud Institute for Molecular Life Sciences Internal grant Mihai G Netea ZonMw Vidi Frank L van de Veerdonk H2020 European Research Council HDM-FUN Frank L van de Veerdonk H2020 European Research Council Solve-RD (No. 779257) Alexander Hoischen The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: We thank the Bioinformatics group of the Genome Diagnostics division of the department of Human Genetics and the Radboud Genomics Technology Center of the Radboud University Medical Center for the sharing, annotation and pseudonymisation of whole exome sequencing datasets of patients and their parents included in this study. Furthermore, we acknowledge all members of the multidisciplinary immunogenetics sign-out meeting of the University Medical Centers from Nijmegen and Maas-tricht. The authors also acknowledge support from several funding parties. MG Netea was supported by an ERC Advanced Grant (No. 833247) and a Spinoza Grant of the Netherlands Organization for Scientific Support. This research was also part of a Radboud Institute for Molecular Life Sciences PhD grant (to M G Netea). F L van de Veerdonk was supported by a ZonMW Vidi grant and HDM-FUN EU H2020. A Hoischen was supported by the Solve-RD project of the European Union’s Horizon 2020 research and innovation programme (No. 779257). Funding This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences. Funding Information: Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI). Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES. Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, nonsynonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease. Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease. Funding: This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences. Publisher Copyright: © Hebert et al.
PY - 2022/10/17
Y1 - 2022/10/17
N2 - Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI).Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES.Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease.Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease.
AB - Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI).Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES.Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease.Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease.
U2 - 10.7554/eLife.78469
DO - 10.7554/eLife.78469
M3 - Article
C2 - 36250618
AN - SCOPUS:85141487334
VL - 11
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e78469
ER -